Survival in MS-based PML Improves, But Disability Still High

Action Points

Explain that survival has improved dramatically for patients with multiple sclerosis who develop progressive multifocal leukoencephalopathy (PML) during treatment with natalizumab (Tysabri).

Note that factors associated with survival in patients with progressive multifocal leukoencephalopathy included younger age and shorter time to diagnosis after symptom onset.

Survival has improved dramatically for patients with multiple sclerosis who develop progressive multifocal leukoencephalopathy (PML) during treatment with natalizumab (Tysabri), a study found.

The survival rate now stands at 71%, researchers reported in the May 17 Neurology.

Survivors were younger, with a median age of 40 compared with a median age of 54 among fatal cases, and had a shorter time to diagnosis after onset of symptoms (44 versus 63 days).

Among 35 patients who developed this rare infection of the central nervous system associated with reactivation of the John Cunningham virus (JCV), 25 remained alive, according to Patrick Vermersch, MD, PhD, of the University of Lille in France, and colleagues.

Natalizumab, a humanized monoclonal antibody against α-4 integrin, was first approved by the FDA for relapsing MS, but was withdrawn after three cases of PML were reported.

It was returned to the market in 2006, and has been given to more than 71,000 patients worldwide.

However, a recent report suggested that many patients consider a one in 1,000 estimated incidence of PML in natalizumab-treated MS to be too risky.

To assess outcomes and explore factors associated with survival and disability, Vermersch's group collected data on the first 35 cases that occurred after natalizumab was reintroduced.

The cohort consisted of 25 women and 10 men with a mean age of 43.7, and a mean MS duration of 12.5 years.

They had been given a mean of 26.6 infusions of natalizumab, and nearly half had received another immunosuppressive agent, such as methotrexate or cyclophosphamide, before natalizumab treatment began.

Because of the high numbers of patients who developed PML after other immunosuppressant treatment, the FDA recently changed the drug's labeling to reflect this risk.

Aside from patient age and time to diagnosis, survival also was associated with patients' having lower mean Expanded Disability Status Scale scores at baseline (a mean of 3.9 versus 4.9).

Among the 31 patients for whom brain MRI was available, in 86% the infection was unilobar or multilobar in survivors, while 70% of the patients who died had widespread disease.

Concentrations of the JCV in cerebrospinal fluid also were lower in surviving patients (121,000 copies per mL versus 412,000 per mL).

Treatment was similar for all patients who developed PML, beginning with rapid removal of the drug with immunoadsorption or plasma exchange.

Some also received mefloquine (Lariam) or mirtazapine (Remeron).

Almost all of the patients developed secondary immune reconstitution inflammatory syndrome (IRIS), which is characterized by brain inflammation that occurs after restoration of the immune system. It was treated with high-dose corticosteroids in most cases, but half of the deaths were thought to be from IRIS.

Other causes of death included aspiration pneumonia and respiratory failure.

Twelve of the surviving patients were left with severe disability, while nine had moderate and four had mild disability.

Severe disability was more common in patients with shorter follow-up time since their diagnosis, at a mean of six months, compared with a mean of 10.4 months in those with mild disability.

The survival rate seen in this series is considerably higher than has been reported in other PML patient populations.

For instance, in one group of transplant recipients, survival was 29%, and in a group of HIV patients only 10% survived; however, this was before the era of highly active antiretroviral therapy.

Patients are more likely to survive if their immune system has remained functional, the researchers explained.

"Therefore, a possible reason for the improved survival seen in natalizumab-associated PML is that these patients have intact, functional immune systems that can be reconstituted," they wrote.

In addition, prescribers and patients today are given extensive information about PML, likely resulting in earlier diagnosis.

Limitations of this analysis include the short follow up and the potential confounding of disability status by deterioration associated with the underlying MS.

"Although PML has traditionally been considered a fatal disease, current data for natalizumab-associated PML challenge this belief," the authors wrote.

In an accompanying editorial, David B. Clifford, MD, of Washington University in St. Louis, emphasized the importance of early diagnosis, which "allows reversing immunosuppression earlier, arresting ongoing viral associated demyelination, and limiting the extent of brain damage."

"Neurologists might well apply the 'time is brain' mantra to this aggressive infectious disease as well as to vascular disease," Clifford wrote.

The lead author is on advisory boards for Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Teva Pharmaceuticals, and sanofi-aventis. He and his co-authors also have received honoraria and research support from Biogen Idec, Teva, Bayer, and a number of other companies.

Three of the authors are employees of Biogen Idec, and own stock or stock options in the company.

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